Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors

• Published in: Cellular and molecular life sciences : CMLS Vol. 69; no. 23; pp. 4041 - 4049
• Main Authors: HoWangYin, Kiave-Yune, Loustau, Maria, Wu, Juan, Alegre, Estibaliz, Daouya, Marina, Caumartin, Julien, Sousa, Sylvie, Horuzsko, Anatolij, Carosella, Edgardo D., LeMaoult, Joel
• Format: Journal Article
• Language: English
• Published: Basel SP Birkhäuser Verlag Basel 01.12.2012; Springer Nature B.V
• Subjects: Animals; Antigens; Antigens, CD - genetics; Antigens, CD - metabolism; beta 2-Microglobulin - metabolism; Binding, Competitive; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cell Biology; Cell Line, Tumor; Cellular biology; Flow Cytometry; Genetic diversity; Graft Survival; HEK293 Cells; HeLa Cells; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; HLA-G Antigens - chemistry; HLA-G Antigens - genetics; HLA-G Antigens - metabolism; Humans; Immunology; Kaplan-Meier Estimate; Leukocyte Immunoglobulin-like Receptor B1; Leukocytes; Life Sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice, Inbred C57BL; Mice, Transgenic; Protein Binding; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Multimerization; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Research Article; Skin Transplantation; Transplantation, Homologous; Inhibitory receptors; Immune regulation; Transplantation; HLA-G
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-012-1069-3

The non-classical Human leukocyte antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions. Most of the known functions of HLA-G concern the membrane-bound HLA-G1 and soluble HLA-G5 isoforms, which present the typical structure of classical HLA class I molecule: a heavy chain of three globular domains α 1 –α 2 –α 3 non-covalently bound to β-2-microglobulin (B2M) and a peptide. Very little is known of the structural features and functions of other HLA-G isoforms or structural conformations other than B2M-associated HLA-G1 and HLA-G5. In the present work, we studied the capability of all isoforms to form homomultimers, and investigated whether they could bind to, and function through, the known HLA-G receptors LILRB1 and LILRB2. We report that all HLA-G isoforms may form homodimers, demonstrating for the first time the existence of HLA-G4 dimers. We also report that the HLA-G α 1 –α 3 structure, which constitutes the extracellular part of HLA-G2 and HLA-G6, binds the LILRB2 receptor but not LILRB1. This is the first report of a receptor for a truncated HLA-G isoform. Following up on this finding, we show that the α 1 –α 3 -Fc structure coated on agarose beads is tolerogenic and capable of prolonging the survival of skin allografts in B6-mice and in a LILRB2-transgenic mouse model. This study is the first proof of concept that truncated HLA-G isoforms could be used as therapeutic agents.